The discovery1b of the dolastatin series1c,d of cancer cell growth inhibitors contained in the wide ranging sea hare Dolabella auricularia revealed a new and very promising vista for anticancer drug discovery. That's proved to be broadly confirmed by clinical development,2 of dolastatin 10 (1) and 152c and structural modifications designated auristatins.3 By 2001, auristatin E (2a)3b began preclinical development as a very promising antibody drug conjugate (ADC) by linkage to a CD30 monoclonal antibody. Soon the development continued, employing the cancer biology equivalent desmethyl auristatin E (2b).

Presently the resulting ADC anticancer drug4a-e designated ADCETRIS has been approved for use in 50 countries, for example, treatment of patients with refractory Hodgkin's lymphoma and large cell lymphoma thereby resulting in remarkable complete remissions.4d Those early clinical results have inspired a massive current research effort to link auristatin (2b) to other monoclonal antibodies4a,b representing a spectrum of cancer types. In parallel, considerable research has been continued to discover structural modifications of dolastatin 10 that would provide powerful cancer cell growth inhibition without the high toxic level, and provide a much better therapeutic range for inspired ADC use. Citation of any reference in this section is not to be construed as an admission that such reference is prior art to the present disclosure.